Mutations in ATP13A2, which encodes a lysosomal P type ATPase, result in KuforRakeb syndrome, an atypical form of Parkinson's disease (PD). Its yeast ortholog, YPK9, has also been shown to protect against a-synuclein and manganese-induced toxicity, established genetic and environmental risk factors for PD, respectively. These observations suggest that ATP13A2 may play an important role in PD pathogenesis, possibly through its influence on lysosomal protein degradation pathways (autophagy) and/or by functioning to sequester manganese, protecting against its neurotoxic effects. We have established an animal model for this rare, familial form of PD by disrupting the Atp13a2 gene in mice. In Aim 1 we will characterize the knockout mice to determine if they exhibit any of the behavioral or neuroanatomical hallmarks of PD such as motor dysfunction and loss of dopaminergic neurons in the nigrostriatal pathway. To achieve this aim wildtype (Atp13a2+/+) and Atp13a2deficient (Atp13a2-/-) mice will be subjected to an array of behavioral assays to assess motor function, learning, and memory and histological analyses to identify alterations in brain neuroanatomy with emphasis placed on the substantia nigra (SN) and globus pallidus (GP), regions known to be affected in sporadic PD and KuforRakeb syndrome, respectively. In Aim 2 we will evaluate the sensitivity of the Atp13a2-/- mice and primary mesencephalic cultures derived from them to manganese, which we anticipate may exacerbate their phenotype relative to controls. Behavioral and histological analyses on mice chronically exposed to manganese will be carried out as described in Aim 1, while cell viability and immunocytochemical assays and measurements of oxidative stress will be performed to assess the sensitivity of neurons in the primary mesencephalic cultures to the toxic effects of manganese. Data obtained from these studies may help establish an important link between genetic and environmental risk factors for PD and improve our understanding of the pathological mechanisms underlying both sporadic and genetic forms of PD. PUBLIC HEALTH RELEVANCE: Parkinson's disease (PD) is the second most common neurodegenerative disorder. We have created a mouse animal model to research a rare, inherited form of this disease called Kufor- Rakeb syndrome. Our findings could lead to new insights into the causes of PD and its treatment.